(1) Field of the Invention
This invention relates to a method of preparing perillyl alcohol and perillyl acetate from beta-pinene oxide. The chemical structures of these compounds are shown below. ##STR1##
(2) Description of the Related Art
In U.S. Pat. No. 5,110,832 Chastain and Sanders showed the monoterpene perillyl alcohol has a wide spectrum of antimicrobial activity against virtually all bacteria and yeast. Because it is readily biodegradable, and considered environmentally safe, it has numerous potential uses as a bactericide and an anti-yeast compound in agricultural, industrial, pharmaceutical, and consumer products. Perillyl alcohol inhibits dental plaque and is likely to be used in mouthwash, toothpaste, and chewing gum. Uses in topical pharmaceutical and veterinary products to control normal and resistent pathogens have been suggested. Perillyl alcohol (A) is an excellent general antiseptic. In laboratory animals perillyl alcohol is non-toxic in bactericidal concentrations and is likely to find utility as a preservative for food, medicine, and cosmetics, and as an antiseptic for food processing equipment. Perillyl alcohol can be used as a bactericide in industrial cutting oils, air filters, and as a spray for bacterial and yeast diseases that infect plants.
In tissue cultures perillyl alcohol was found to have excellent antineoplastic activity against carcinomas of the breast, pancreas, lung, and colon. Antineoplastic concentrations of perillyl alcohol, when administered orally, were demonstrated to be non-toxic in dogs and rats. Gould et all found perillyl acetate to exhibit significant antineoplastic activity in treating and preventing carcinoma of the breast in rats. D. McNamee's pharmacokinetics studies suggested that perillyl alcohol may be a procompound that acts via its metabolites.
Recent efforts of the Environmental Protection Agency to rid the environment of formaldehyde makes perillyl alcohol an ideal candidate as a general disinfectant and as an embalming fluid. When added to hydrocortisone cream, perillyl alcohol will likely find efficacy as a topical bactericide, anti-yeast and antipruritic cream.
Perillyl alcohol, the main ingredient of lavender oil, is obtained from a hybrid of true lavender and spike lavender plants. It has enjoyed a prominent position in both the cosmetic and the perfume industry because it blends well with other essential oils, improves the texture of cosmetics and has virtually no odor. Synthetic perillyl alcohol has been costly and used only in the most expensive perfumes.
In the future, large quantities of perillyl alcohol will be needed for use as microbicides, as antineoplastic agents, as preservatives, and for use in perfumes and fragrances.
Blumann in Chemical Abstracts, Volume 63 1965 on page 1819, produced perillyl alcohol by the oxidation of limonene, and Bardychev substantiated that perillyl alcohol can be produced by the oxidation of limonene as outlined in Chemical Abstracts, Volume 80, 1974, page 359. In German Offen 2,513,910 and Canadian Patent No. 1,077,959 H. R. Ansari and P. Fido produced perillyl alcohol by the acetylation of limonene.
Perillyl alcohol can be produced by reacting limonene with selenium dioxide (that is toxic) and other oxidants (that are difficult to work with i.e., anhydrous chromium trioxide) to yield various oxidation products, including a small amount of perillaldehyde. Once isolated, perillaldehyde is reduced to afford perillyl alcohol. While this two-step process is conceptually attractive, the oxidation of limonene to give perillyl alcohol proceeds in a low overall yield.
Several routes have been have been developed to produce perillyl alcohol from beta pinene. For example, Walling made perillyl alcohol (Canadian Patent No. 981,695) by reacting benzyl peroxide with beta pinene followed by alkaline hydrolysis to perillyl alcohol. In 1967 a process for preparing perillyl alcohol was described in British Patent 1,094,875 (Nippon Terpene) wherein beta pinene was oxidized by lead tetracetate in the presence of fatty acid dissolved in glacial acetic acid that was subsequently hydrolyzed to perillyl alcohol with a yield of only forty-five (45%) percent. Similarly, beta pinene was oxidized with Pb.sub.3 O.sub.4 in glacial acetic acid to form perillyl alcohol (Barton et al. J. Clem. Soc. Perkin Trans. I 614 1972). In 1972 in German Offen 2,162,882, M. Julia made perillyl alcohol by oxidizing beta pinene with a benzoxyloxy radical, generated by ammonium persulfate oxidation of a benzoate anion.
Among other routes that have been developed to prepare perillyl alcohol from beta pinene oxide is that reported by T. K. Keenan in 1966 who produced perillyl acetate from beta-pinene oxide by refluxing beta-pinene oxide with acetic anhydride and acetic acid for seven hours followed by removal of the acetate to afford a nine percent (9%) yield of perillyl alcohol based on the starting beta-pinene oxide (B.S. Thesis Mass. Institute of Tech.). The applicants found the process to be reproducible albeit in low yield. F. C. Delay in Swiss Patent 5671/84 reported the production of perillyl alcohol in which he treated beta-pinene oxide with nitromethane and ammonium nitrite at a temperature between 20.degree. C. and 90.degree. C. in an overall yield of thirty percent (30%). Two years later Wang and co-workers published in Tetrahedron 1986, 620-638 complete details of this procedure and reported an overall yield of sixty-eight percent (68%) perillyl alcohol.
In 1980 Lazare and co-workers reported a ninety percent (90%) yield of a diol that was obtained by treating beta-pinene oxide with mercury (II) salts in tetrahydrofuran/water solutions. (J. Chem. Soc. Perkin Trans I 1980, 1747). The diol was extracted with chloroform followed by its reaction with 1.5 N. hydrochloric acid to give an eighty-five percent (85%) yield of perillyl alcohol based on the initial beta pinene oxide. The applicants could not reproduce the acid-catalyzed dehydration using 1.5 N HCl despite trying numerous variations of the experimental conditions reported. The applicants found this process to produce perillyl alcohol in a yield of less than ten percent. In every case complex mixtures of products were obtained. It was stated that both p-menth-1-ene-7, 8 diol and 7-acetoxy-p-menth-1-en-8-ol are fragrance compounds but no experimental procedures describing their preparation were presented.
In 1986 Ohloff and Giersch (Helv. Chim. Acta 1980 63, 83) prepared p-menth-1-ene-7, 8-diol in high yield by stirring beta-pinene oxide in water and then continuously adding solid carbon dioxide to the mixture. This reaction is pH dependent, requires very careful monitoring to prevent serious workup problems, and is considered a poor commercial process. The p-menth-1-ene-7, 8-diol produced in this fashion was used for purposes other than preparing perillyl alcohol.